[Circadian rhythms and depression]. / Störung zirkadianer Rhythmen im Kontext depressiver Erkrankungen.

Depressive disorders are associated with various neurobiological alterations like hyperactivity of the hypothalamic-pituitary-adrenal axis, altered neuroplasticity and altered circadian rhythms. Relating to the circadian symptoms, a process is adopted in which individual genetic factors together with social, psychological and physical stressors may lead to a decompensation of the circadian system. The causal connections between depressive disorders and disturbed circadian rhythms have not been completely clarified. Chronobiological therapy is based on these disturbed processes. For the treatment of the circadian symptoms, various scientifically tested chronotherapeutics are available with however different effectiveness and evidence like light therapy or sleep deprivation. The successful treatment of depression also frequently leads to a improvement in altered circadian rhythm.

Nutrigenetics and Nutrimiromics of the Circadian System: The Time for Human Health.

Even though the rhythmic oscillations of life have long been known, the precise molecular mechanisms of the biological clock are only recently being explored. Circadian rhythms are found in virtually all organisms and affect our lives. Thus, it is not surprising that the correct running of this clock is essential for cellular functions and health. The circadian system is composed of an intricate network of genes interwined in an intrincated transcriptional/translational feedback loop. The precise oscillation of this clock is controlled by the circadian genes that, in turn, regulate the circadian oscillations of many cellular pathways. Consequently, variations in these genes have been associated with human diseases and metabolic disorders. From a nutrigenetics point of view, some of these variations modify the individual response to the diet and interact with nutrients to modulate such response. This circadian feedback loop is also epigenetically modulated. Among the epigenetic mechanisms that control circadian rhythms, microRNAs are the least studied ones. In this paper, we review the variants of circadian-related genes associated to human disease and nutritional response and discuss the current knowledge about circadian microRNAs. Accumulated evidence on the genetics and epigenetics of the circadian system points to important implications of chronotherapy in the clinical practice, not only in terms of pharmacotherapy, but also for dietary interventions. However, interventional studies (especially nutritional trials) that include chronotherapy are scarce. Given the importance of chronobiology in human health such studies are warranted in the near future.

Sleep- and circadian rhythm-associated pathways as therapeutic targets in bipolar disorder.

INTRODUCTION: Disruptions in sleep and circadian rhythms are observed in individuals with bipolar disorders (BD), both during acute mood episodes and remission. Such abnormalities may relate to dysfunction of the molecular circadian clock and could offer a target for new drugs. AREAS COVERED: This review focuses on clinical, actigraphic, biochemical and genetic biomarkers of BDs, as well as animal and cellular models, and highlights that sleep and circadian rhythm disturbances are closely linked to the susceptibility to BDs and vulnerability to mood relapses. As lithium is likely to act as a synchronizer and stabilizer of circadian rhythms, we will review pharmacogenetic studies testing circadian gene polymorphisms and prophylactic response to lithium. Interventions such as sleep deprivation, light therapy and psychological therapies may also target sleep and circadian disruptions in BDs efficiently for treatment and prevention of bipolar depression. EXPERT OPINION: We suggest that future research should clarify the associations between sleep and circadian rhythm disturbances and alterations of the molecular clock in order to identify critical targets within the circadian pathway. The investigation of such targets using human cellular models or animal models combined with 'omics' approaches are crucial steps for new drug development.

Behavioral therapy reverses circadian deficits in a transgenic mouse model of Huntington's disease.

Progressive disruption of circadian rhythmicity associated with disturbance of the sleep-wake cycle is one of the most insidious symptoms of Huntington's disease (HD) and represents a critical management issue for both patients and their care takers. The R6/2 mouse model of HD shows a progressive disruption of the circadian rhythmicity at both behavioral and molecular levels, although the intrinsic cellular machinery that drives circadian rhythmicity in individual cells appears to be fundamentally intact. Circadian rhythms are controlled by a master clock located in the suprachiasmatic nuclei (SCN) and can be synchronized by light and non-photic factors such as exercise. Here, we aimed to test whether or not stimulating the SCN directly could prevent the loss of circadian rhythmicity in R6/2 mice. We used combinations of bright light therapy and voluntary exercise as our treatment regimes. We found that all treatments had some beneficial effects, as measured by delayed disintegration of the rest-activity rhythm and improved behavioral synchronization to the light-dark cycle. The best effects were observed in mice treated with a combination of bright light therapy and restricted periods of voluntary exercise. Neither the cause nor the consequence of deteriorating sleep-wake activity in HD patients is known. Nevertheless, our findings can be translated immediately to human patients with little cost or risk, since both light therapy and restricted exercise regimes are non-pharmacological interventions that are relatively easy to schedule. Improved circadian rhythmicity is likely to have beneficial knock-on effects on mood and general health in HD patients. Until effective treatments are found for HD, strategies that reduce deleterious effects of disordered physiology should be part of HD patient treatment programs.

[Affective disorders: News in chronobiological models]. / Troubles affectifs : actualité des modèles chronobiologiques.

Good news on chronobiological models of affective disorders are coming from a therapeutic innovation in the field of antidepressive action. Coming back to fundamentals by reconsidering the importance of the role of biological rhythms impairment in dysthymic pathology, a new interest bored on studies exploring short periodicities, so-called "ultradian" ones, on the basis of pharmacodynamics in the concept of therapeutic "window" of administration. The priority of circadian rhythms due to the major external biological desynchronization in depression, as well as the importance of sleep and alertness pathology, the spectacular relief of the depressive mood upon sleep deprivation, and the strong reduction of sleep need in mania, delayed exploration of ultradian exaltation of harmonic circadian components, marking a "buzz" of rhythmic structure and calling a "chronobiotic compound" which would be able to apply a "reset" to the temporal organisation. Another return to the origin leads to the experimental genomics, informing nor the "depressivity" but manic pathogenesis, in a mouse gene model which queries on the share of addictive and affective disorders.

Circadian disruption, Per3, and human cytokine secretion.

Circadian disruption has been linked with inflammation, an established cancer risk factor. Per3 clock gene polymorphisms have also been associated with circadian disruption and with increased cancer risk. Patients completed a questionnaire and provided a blood sample prior to undergoing a colonoscopy (n = 70). Adjusted mean serum cytokine concentrations (IL-6, TNF-alpha, gamma-INF, IL-1ra, IL-1-beta, VEGF) were compared among patients with high and low scores for fatigue (Multidimensional Fatigue Inventory), depressive symptoms (Beck Depression Inventory II), or sleep disruption (Pittsburgh Sleep Quality Index), or among patients with different Per3 clock gene variants. Poor sleep was associated with elevated VEGF, and fatigue-related reduced activity was associated with elevated TNF-alpha concentrations. Participants with the 4/5 or 5/5 Per3 variable tandem repeat sequence had elevated IL-6 concentrations compared to those with the 4/4 genotype. Biological processes linking circadian disruption with cancer remain to be elucidated. Increased inflammatory cytokine secretion may play a role.

[Biology and genetics of circadian rhythm]. / Biologie et génétique des rythmes circadiens.

In recent decades our knowledge of the molecular mechanisms of biological clocks has grown expontentially. This has helped to guide the choice of genes studied to explain inter-individual variations seen in circadian rhythms. In recent years analysis of circadian rhythms has advanced considerably into the study of pathological circadian rhythms in human beings. These findings, combined with those obtained from studying mice whose circadian genes have been rendered incapable, have revealed the role of genetic factors in circadian rhythms. This literature review presents an overview of these findings. Beyond our understanding of the functioning of these biological clocks, this knowledge will be extremely useful to analyse genetic factors involved in morbid conditions involving circadian rhythm abnormalities.

The multifaceted role of inhibition in epilepsy: seizure-genesis through excessive GABAergic inhibition in autosomal dominant nocturnal frontal lobe epilepsy.

PURPOSE OF REVIEW: While epilepsy describes a heterogeneous array of syndromes, the conventional view is that there is a common underlying failure in the ability of GABAergic inhibition to overcome excessive synaptic excitation. This review explores the possibility that enhanced GABAergic inhibition in the neocortex could also be proepileptogenic. RECENT FINDINGS: Recently, two mouse strains carrying mutant alleles of the alpha4 subunit of the nicotinic acetylcholine receptor that are associated with autosomal dominant nocturnal frontal lobe epilepsy have been found to show spontaneous seizures. Recordings from neocortical pyramidal neurons in vitro show that the autosomal dominant nocturnal frontal lobe epilepsy mutations are associated with large selective increases in nicotine-evoked GABAergic inhibition, which may be key factor in epileptogenesis, as the seizures in vivo are blocked by subconvulsive doses of the GABAA receptor antagonist, picrotoxin. SUMMARY: The precise links between the observed gain of neocortical inhibition and development of seizures in autosomal dominant nocturnal frontal lobe epilepsy mice remain unknown. Recent insights into the functional properties of cortical GABAergic circuits, however, suggest several possible pathways to be explored, whose elucidation could enable selective therapeutic interventions.

Prenatal ethanol exposure alters the expression of period genes governing the circadian function of beta-endorphin neurons in the hypothalamus.

Sleep-wake disturbances and stress hyper-responsiveness have been observed in human neonates, children and adolescents who were exposed to alcohol during the prenatal period. Using the laboratory rat as an animal model, we investigated whether fetal ethanol exposure during gestational days 10-21 affects the circadian function of the stress-axis regulatory beta-endorphin neurons in the hypothalamus. Fetal ethanol-exposed rats showed abnormality in the circadian expression of proopiomelanocortin (POMC) mRNA encoding the peptide beta-endorphin in the arcuate nucleus of the hypothalamus during the adult period. These rats also showed altered circadian expression of the clock governing Period genes rPer1, rPer2 and rPer3, in the arcuate nucleus, and rPer1 and rPer 2 mRNA levels in the suprachiasmatic nucleus. Laser captured microdissection analysis identified constitutive expression of rPer1, rPer2 and rPer3 genes in beta-endorphin-containing neurons. These data suggest for the first time that fetal exposure to ethanol significantly alters the clock mechanisms governing the circadian function of beta-endorphin neurons.

Molecular-timetable methods for detection of body time and rhythm disorders from single-time-point genome-wide expression profiles.

Detection of individual body time (BT) via a single-time-point assay has been a longstanding unfulfilled dream in medicine, because BT information can be exploited to maximize potency and minimize toxicity during drug administration and thus will enable highly optimized medication. To achieve this dream, we created a "molecular timetable" composed of >100 "time-indicating genes," whose gene expression levels can represent internal BT. Here we describe a robust method called the "molecular-timetable method" for BT detection from a single-time-point expression profile. The power of this method is demonstrated by the sensitive and accurate detection of BT and the sensitive diagnosis of rhythm disorders. These results demonstrate the feasibility of BT detection based on single-time-point sampling, suggest the potential for expression-based diagnosis of rhythm disorders, and may translate functional genomics into chronotherapy and personalized medicine.